Compositions and methods for treating conditions of the nail unit

ABSTRACT

The biodegradable drug delivery systems described here are formulated for implantation into the nail unit and its surrounding tissues for the treatment of various nail unit conditions. The systems include non-temperature dependent phase change compositions that may be formulated as solutions, solids, semisolids, microparticles, or crystals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. application Ser. No.11/302,014, filed Dec. 12, 2005, which claims priority to U.S.Provisional Application No. 60/593,106, filed Dec. 10, 2004, each ofwhich is hereby incorporated herein by reference their entirety.

FIELD

The compositions and methods described here are in the field of drugdelivery. More specifically, the described compositions and methodsrelate to localized delivery of active agents to the nail unit and itssurrounding tissues.

BACKGROUND

There are a variety of conditions that can affect the human nail. Forexample, the nail may be afflicted by inflammatory conditions such aspsoriasis and lichen planus; nail tumors such as glomus tumor or digitalmyxoid cyst; and infections such as paronychia and onychomycosis. Thepathophysiology of each condition is closely tied to nail structure andfunction. Thus, an understanding of nail anatomy and function isnecessary in developing therapy for nail conditions.

In brief, the human nail is a modified cutaneous structure oftendescribed as a unit comprising several parts: the nail matrix, the nailbed, the nail plate, the nail folds, and the cuticle. The nail matrix islocated beneath the proximal nail fold, and is the germinative portionof the nail unit that produces the nail plate. The nail bed is a layerof epithelium lying between the lunula (the portion of the nail matrixusually visible as a gray-white half moon projecting just distal to theproximal nail-fold cuticle) and the hyponychium (the distal epitheliumat the free edge of the nail). The nail plate (fingernail or toenail) isproduced by the matrix and progresses toward the tip of the fingers ortoes as new plate is formed. The cutaneous tissue framing the nail unit,and which invaginates proximal and lateral to the nail plate, isreferred to as the nail folds. The primary function of the nail plate isto protect the underlying digit, but fingernails and toenails are oftenalso cosmetically important for many patients.

Nail infections are common conditions of the nail. Onychomycosis, afungal infection of the nail bed, matrix, or nail plate, is the mostcommon nail infection. The primary clinical features of onychomycosisare distal onycholysis (separation of the nail plate from the nail bed),subungual hyperkeratosis, and a dystrophic, discolored nail. Patientsafflicted with onychomycosis are usually embarrassed by their naildisfigurement, but the infection is more than a cosmetic problem. It cansometimes limit mobility and indirectly decrease peripheral circulation,thereby worsening conditions such as venous stasis and diabetic ulcers.Fungal infections of the nail can also spread to other areas of the bodyand potentially to other persons. The fungal infection can be caused bydermatophytes (e.g., Trichophyton rubrum and T. mentagrophytes), but mayalso be due to infection by Candida species or nondermatophyte moldssuch as Aspergillus species, Scopulariosis brevicaulis, Fusariumspecies, and Scytalidium species.

Currently, oral antifungal agents are the mainstay of treatment foronychomycosis. For example, ketoconazole, Sporonox® capsules(itraconazole) (Janssen Pharmaceutica Products, L.P., Titusville, N.J.and Ortho Biotech Products, L.P., Raritan, N.J.), Lamisil® tablets(terbinafine hydrochloride) (Novartis Pharmaceuticals, East Hanover,N.J.), Diflucan® tablets (fluconazole) (Pfizer, New York, N.Y.), andoral griseofulvin are commonly prescribed antifungal agents. However,these oral antifungal products are associated with many minor systemicside effects such as headaches, stomach upset, skin rashes, andphotosensitivity, as well as serious systemic side effects such as heartfailure and liver failure. Furthermore, Fluconazole is not approved bythe U.S. Food and Drug Administration (FDA) for the treatment of fungalnail infections. Moreover, although oral antifungal therapy ispreferred, associated cure rates are not high and relapse is common. Theprolonged treatment regimen of one dose daily for at least three months,or once weekly for nine to twelve months also leads to poor patientcompliance with oral antifungal therapy.

Topical therapy with antifungal agents such as fluconazole,ketoconazole, miconazole, terbinafine, tolnaftate, and undecylenicalkanolamide is an alternative for patients in whom oral antifungaltherapy is contraindicated. A topical solution, Penlac® nail laquer(ciclopirox solution, 8%) (Dermik Laboratories, Berwyn, Pa.), has alsorecently been approved by the FDA for the topical treatment of mild tomoderate onychomycosis. However, the topical mode of administration isseldom effective to treat more than mild nail unit infections becausethe active agent is unable to effectively penetrate the nail. Topicaltherapy accompanied by chemical or physical abrasion of the nails hasalso been largely unsuccessful. Topical antifungal therapy usually alsoinvolves daily application to the nails for several months, and thus,also poses a compliance problem.

Other regimens for treating onychomycosis are described by Birnbaum etal. in U.S. Publication No. 2004/0062733 and Jackson et al. in U.S.Publication No. 2005/0042293. Specifically, in Birnbaum et al., theantifungal agent is placed under the fingernails by scraping themagainst a semi-solid, e.g., a bar of soap, or by injection of the agentunder the nail plate through the hyponychium. In Jackson et al., aliquid or paste formulation of terbinafine is injected subcutaneouslybelow the fungal infection. The liquid or paste then solidifies uponreaching body temperature. Jackson et al. describe their formulations ascapable of delivering a high dose of drug over a short time period byusing a lower drug load.

Accordingly, it would be desirable to have a drug delivery system fordelivering antifungal agents and other active agents locally to the nailunit and its surrounding tissues for treatment of nail unit conditions.It would also be desirable to have a drug delivery system that can beprecisely delivered to the portion of the nail unit that requirestreatment. Similarly, it would be desirable to have drug deliverysystems that simplify treatment regimens and improve patient compliance.

BRIEF SUMMARY

Described here are drug delivery systems and methods for treatingconditions of the nail unit. The drug delivery systems include atherapeutically effective amount of a composition having an active agentfor local sustained release useful for treating a nail unit condition.The compositions/drug delivery systems are usually configured forimplantation in a nail unit and provide local sustained release of theactive agent to treat conditions of the nail unit. The compositions/drugdelivery systems are formulated such that they do not undergo a phasechange with changes in temperature.

The drug delivery systems may be formulated as a solid, a liquid, asemisolid, microparticles, nanoparticles, or crystals. If a carrier isincluded, the choice of carrier will usually depend on such factors asthe form of system, specific active agent used, and the intendedduration of treatment. However, in all instances the carrier will bebiocompatible. In one variation, the carrier is biodegradable. Inanother variation, the carrier is bioerodible. In yet another variation,the carrier is bioabsorbable.

Various active agents may be incorporated into the drug deliverysystems, including, but not limited to, proteins, peptides, nucleicacids, small molecules, or other factors that stimulate nail or othertissue growth and regeneration, stimulate angiogenesis, enhance bloodsupply or circulation, and/or modulate the immune system, reducescarring, or improve healing. In one variation, antifungal agents,including, but not limited to, amorolfine; ciclopirox; flucytosine;griseofulvin; haloprogrin; potassium iodide sodium pyrithione;undecylenic acid; imidazole derivatives, including without limitationbifonazole, butoconazole, clotrimazole, econazole, ketoconazole,miconazole, oxiconazole, and sulconazole; triazoles, including withoutlimitation itraconazole, fluconazole, and terconazole; allylamines,including without limitation naftifine and terbinafine, terbinafine FB;polyene antifungal antibiotics such as amphotericin B and nystatin;antifungal organic acids such as benzoic acid, salicylic acid, propionicacid, caprylic acid; and derivatives thereof may be used. In onevariation, the antifungal agent may be combined with one or moreadditional antifungal agents. In another variation, the antifungal agentmay be combined with one or more active agents from a different drugclass. For example, the antifungal agent may be combined with one ormore active agents including, but not limited to, an antibiotic agent, asteroidal anti-inflammatory agent, an analgesic, or an anesthetic.

The drug delivery systems may be used to treat various nail unitconditions. Examples of such nail unit conditions include, but are notlimited to, medical conditions such as infections, inflammation, andtumors. Examples of nail infections include, but are not limited to,distal and lateral subungual onychomycosis, endonyx onychomycosis, whitesuperficial onychomycosis, proximal subungual onychomycosis, totaldystrophic onychomycosis, Candida onychomycosis, and paronychia.Examples of nail inflammation include, but are not limited to thoseconditions associated with inflammatory diseases such as psoriasis andlichen planus. Examples of nail tumors include, but are not limited to,glomus tumor, digital myxoid (mucus) cyst, subungual exostosis, andperiungual angiofibromas. The drug delivery systems may also be used totreat cosmetic nail conditions such as pitting, brittleness, ordiscoloration. In one variation, the drug delivery systems may be usedin combination with other conventional methods of treating nail unitconditions.

In general, the method for treating a nail unit condition includesadministering locally within any portion of a digit, e.g., the distalportion, the proximal portion, and/or the middle portion, a compositionhaving a therapeutically effective amount of an active agent. The drugdelivery systems may be placed using a variety of methods, including,but not limited to, placement by forceps, placement through conduitssuch as trocars and needles, and placement using applicators configuredto drive the system directly into the skin.

DETAILED DESCRIPTION

Described here are compositions and methods for treating conditions ofthe nail unit. The nail unit is located at the distal portion of thedigits (i.e., tips of the fingers and toes). As used herein, the term“nail unit” refers to the nail matrix, nail plate, nail bed, nail folds,and cuticle, in combination, and the tissues adjacent to thosestructures in the distal phalanx. Examples of such adjacent tissuesinclude epidermal tissue, dermal tissue, subcutaneous tissue (includingadipose tissue), muscle, tendon, and bone in the region of the digitfrom the distal interphalangeal joint (or the distal-mostinterphalangeal joint) to the tip of the digit. As used herein, the term“nail unit condition” refers to a medical or cosmetic conditionaffecting any part of the nail unit. Furthermore, as used herein, theterm “treat”, “treating”, or “treatment” refers to the resolution orreduction of symptoms or the underlying cause of the nail condition,prevention of a nail condition, or prevention of sequelae of a nailcondition. The terms “nail” or “nail plate” are herein usedinterchangeably, and refer to fingernails or toenails.

The compositions may be of varying form. In one variation, thecomposition includes an active agent for the local treatment of a nailunit condition and a pharmaceutically acceptable carrier or matrixmaterial. By “pharmaceutically acceptable” it is meant a substance thatis biocompatible and can be administered to a patient without causingsignificant undesirable physiological effects, and a substance that doesnot interact in a significantly deleterious manner with any of the othercomponents of the formulation in which it is contained. In anothervariation, the composition takes a pure crystalline form, and does notinclude a carrier or matrix material.

The compositions are also generally formulated for percutaneous deliveryto the nail unit, and for sustained release of the active agent. Theymay be formulated to have drug loads of any amount. Once administered,the compositions release an active agent to treat a nail unit conditionover time periods of less than one week, at least about one week, atleast about two weeks, at least about four weeks, at least about eightweeks, or at least about twelve weeks or more.

Compositions. As mentioned above, the compositions (drug deliverysystems) described here may take varying forms, e.g., a solid, asemisolid, a solution, an emulsion, a non-temperature dependent phasechange composition, microparticles, nanoparticles, crystals, and thelike, depending on such factors as the particular active agent used, thetype of nail condition being treated, and the medical history of thepatient. However, in all instances, they are made to contain a drug loadcapable of delivering a therapeutically effective amount of an activeagent to treat a nail unit condition. By “therapeutically effectiveamount” it is meant an amount of active agent effective to treat a nailunit condition. Furthermore, as used herein, the term “non-temperaturedependent phase change composition” refers to a composition that doesnot undergo a phase transition, e.g., a transition between the solid,semi-solid, and liquid phases, due to a change in temperature.

The drug delivery systems described here may be delivered in any size,shape, and/or volume compatible with the site of implantation, as longas the systems have the desired drug loading and release kinetics, anddeliver an amount of active agent that is therapeutic for the intendednail condition. For example, the solid drug delivery systems may beformed as particles, sheets, discs, filaments, rods, and the like. Thesolid systems may be formed to have volumes from between about 0 mm³ toabout 20 mm³, between about 5.0 mm³ to about 20 mm³, between about 10mm³ to about 20 mm³, or between about 15 mm³ to about 20 mm³. However,in one variation, the volume may be greater than 20 mm³.

In one variation, the drug delivery system is formulated as a solidimplant and includes active agent generally dispersed in a biocompatiblecarrier or matrix material (Examples 13-19). The carrier or matrixmaterial may be any biocompatible polymeric or nonpolymeric material.The biocompatible materials may also be biodegradable, bioerodible, orbioabsorbable. As used herein, the term “biocompatible” refers to acarrier or matrix material that does not cause significant tissueirritation at the target site. The term “biodegradable” refers tocarrier or matrix material that degrades over time by enzymatic orhydrolytic action, or other mechanism at the target site. By“bioerodible,” it is meant that the carrier or matrix material erodes ordegrades over time by contact with surrounding tissue fluids, throughcellular activity or other physiological degradation mechanisms. By“bioabsorbable,” it is meant that the carrier or matrix material breaksdown and is absorbed by a cell, tissue, or other physiologic mechanism.

If a biocompatible polymer matrix is to be employed, selection of thematrix material will vary depending on the desired release kinetics,formulation constraints, the nature of the condition to be treated, andthe like. Polymer characteristics that are considered include, but arenot limited to, compatibility with the active agent of interest andprocessing temperatures. The biocompatible polymer matrix usuallycomprises less than about 70, less than about 65, less than about 60,less than about 55, less than about 50, less than about 45, less thanabout 40, less than about 35, less than about 30, less than about 25,less than about 20, less than about 10, less than about 15, less thanabout 10, less than about 5, less than about 2.5, or about zero weightpercent of the drug delivery system. In one variation, the biocompatiblepolymer comprises about zero percent by weight of the drug deliverysystem. In another variation, the biocompatible polymer matrix comprisesabout 30% by weight of the drug delivery system.

Biocompatible polymer matrices which may be employed include, but arenot limited to, poly(lactide)s; poly(glycolide)s;poly(lactide-co-glycolide)s; poly(lactic acid)s; poly(glycolic acid)s;poly(lactic acid-co-glycolic acid)s; poly(caprolactone)s;poly(orthoester)s; poly(phosphazene)s; poly(phosphoester)s;poly(hydroxybutyrate)s or copolymers including poly(hydroxybutyrate);poly(lactide-co-caprolactone)s; polycarbonates; polyesteramides;polyanhidrides; poly(dioxanone)s; poly(alkylene alkylate)s; copolymersof polyethylene glycol and a polyorthoester; biodegradablepolyurethanes; poly(amino acid)s; polyetheresters; polyacetals;polycyanoacrylates; poly(oxyethylene)/poly(oxypropylene) copolymers; orblends, copolymers, and mixtures thereof.

In one variation, copolymers of glycolic and lactic acid are used. Thepercent of each monomer in poly(lactic-co-glycolic)acid (PLGA) copolymermay be 0-100%, about 15-85%, about 25-75%, or about 35-65%. If desired,a 50/50 PLGA copolymer may be employed. End-capped (e.g., acid-capped orester-capped) or uncapped PLGA, or a combination of the two forms mayalso be used.

Other matrix forming materials that may be used alone or in combinationwith the biocompatible polymers mentioned above, include, but are notlimited to, polyethylene glycol (PEG), vitamin E and its derivatives,dimethyl sulfone (MSM), carbamide, and blends and mixtures thereof.Natural polysaccharides such as chitosan, alginate, gelatin, and thelike, may also be employed. Furthermore, extracellular matrix componentssuch as collagen, laminin, hylauronic acid, and the like, may be used.In one variation, PEG is used as the matrix forming material. Theamounts of these matrix forming materials incorporated in the drugdelivery systems are usually the same as that described forbiocompatible polymer matrices. In one variation, the drug deliverysystem comprises about 20% PEG as the matrix forming material.

In another variation, the solid drug delivery system may be formed bythe following method. Two grams of Pharmacoat 606(hydroxypropylmethylcellulose) (Shin-Etsu Chemical Co., Ltd., Tokyo,Japan) are wetted with 2.0 g of water. To that paste is added 3.0 g ofmicroparticles made as described below, of the size fraction range ofabout 250 to about 300 microns. After thorough mixing, the resultingpaste is then molded into a flat film of about 0.5 mm thickness using acarver press. The pressed film is then cut into about 1.0 mm², about 2.0mm², or about 5.0 mm² discs using thin walled Teflon straws.Square-based columns can also be cut from the film of desired length andwidth by first trimming the pressed film and then cutting it to thedesired width. The discs or square-based rod like systems are then driedovernight in a vacuum oven.

When the drug delivery system is formulated as microparticles, any oneof the above-described polymers may be used. For example, PLGA may beemployed. Large microparticles are usually prepared using a solventevaporation process. In general, the solvent evaporation processinvolves emulsifying a polymer solution containing the drug in a secondphase using a variety of different agitation techniques to create smalldroplets. The second or continuous phase consists of an emulsifier in alow volatility solvent that is also a poor solvent for the components ofthe first phase. During the evaporation of the highly volatile solventoff the first phase, the polymer and drug-containing droplets solidify.These formed microparticles are then separated by filtration from thecontinuous phase solvent and washed to remove remaining emulsifier.

Volume of the continuous phase, vessel and stirrer geometry, stir rate,concentration of emulsifier, volume and viscosity of the discontinuousphase, etc., are all important factors that influence the final particlesize distribution, while the polymer depot material to drug ratio andthe polymer depot chemistry define the biodegradation and agent releaserate. Microparticle size may be tailored to the release profile ormethod of delivery desired.

When formulated as a semisolid, the drug delivery system will usually bea semisolid emulsion, a gel, or a paste. Semisolid emulsions are eitheroil-in-water or water-in-oil emulsions. Gels are typicallysuspension-type systems. Single-phase gels contain gelling agentsdistributed substantially uniformly throughout the carrier liquid, whichis typically aqueous, but which may also contain an alcohol and,optionally, an oil. Examples of gelling agents that may be used include,but are not limited to, crosslinked acrylic acid polymers such as thecarbomer family of polymers, e.g., carboxypolyalkylenes that may beobtained commercially under the Carbopol™ trademark; hydrophilicpolymers such as polyethylene oxides, polyoxyethylene-polyoxypropylenecopolymers, and polyvinylalcohol; cellulosic polymers such ashydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose, hydroxypropyl methylcellulose phthalate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; andgelatin. In order to prepare a uniform gel, dispersing agents such asalcohol or glycerin can be added, or the gelling agent can be dispersedby trituration, mechanical mixing or stirring, or combinations thereof.Pastes are semisolid dosage forms in which the active agent is suspendedin a suitable base. Depending on the nature of the base, pastes aredivided between fatty pastes or those made from single-phase aqueousgels. The base in a fatty paste is generally petrolatum or hydrophilicpetrolatum or the like. The pastes made from single-phase aqueous gelsgenerally incorporate carboxymethylcellulose or the like as a base.

Active Agents. As used herein, the terms “active agent” and “drug” areused interchangeably and refer to any substance used to treat conditionsof the nail. The active agents generally used in the drug deliverysystems described here include, but are not limited to, analgesics(narcotic and non-narcotic analgesics), anesthetics, anti-infectiveagents, anti-inflammatory agents, chemotherapeutic agents, other smallmolecules, and combinations thereof. Anti-infective agents generallyinclude antibacterial agents, antifungal agents, antiviral agents, andantiseptics. Examples of anti-inflammatory agents include nonsteroidalanti-inflammatory agents and steroidal anti-inflammatory agents.Examples of chemotherapeutic agents include alkaloids, alkylatingagents, antineoplastic antibiotics, and antimetabolites. Nucleic acids,peptides, and proteins are other classes of active agents that may beused.

Examples of antifungal agents that may be incorporated into the drugdelivery systems include amorolfine; ciclopirox; flucytosine;griseofulvin; haloprogrin; potassium iodide sodium pyrithione;undecylenic acid; imidazole derivatives, including without limitationbifonazole, butoconazole, clotrimazole, econazole, ketoconazole,miconazole, oxiconazole, and sulconazole; triazoles, including withoutlimitation itraconazole, fluconazole, and terconazole; allylamines,including without limitation naftifine, terbinafine, and terbinafine FB;polyene antifungal antibiotics such as amphotericin B and nystatin;antifungal organic acids such as benzoic acid, salicylic acid, propionicacid, caprylic acid; and derivatives and combinations thereof.

The choice of a particular antifungal agent will be readily apparent tothose skilled in the art. For example, dermatophyte onychomycosis may betreated by an antifungal agent effective against dermatophytes, such asterbinafine. As another example, a case of onychomycosis of uncertainfungal etiology may be treated with a broad-spectrum antifungal agenteffective against dermatophytes, nondermatophyte molds, and yeasts, suchas itraconazole.

The active agent may constitute from greater than about 30%, fromgreater than about 35%, from greater than about 40%, from greater thanabout 45%, from greater than about 50%, from greater than about 55%,from greater than about 60%, from greater than about 65%, from about70%, from greater than about 75%, from greater than about 80%, fromgreater than about 85%, from greater than about 90%, from greater thanabout 95%, or about 100% by weight of the drug delivery system. In onevariation, the active agent comprises greater than 100% of the drugdelivery system. Drug loading may be varied to achieve high initial drugrelease (burst release). In one variation, the active agent comprisesabout 70% by weight of the drug delivery system.

The total dose delivered for an active agent will vary, depending onsuch factors as the type of nail unit condition being treated, theactive agent used, and duration of therapy. The dosing regimen will alsodepend on factors such as the type of nail unit condition being treated,severity of the nail unit condition, and specific active agent used, butwill usually involve delivery of the active agent in an amount capableof treating the nail unit condition over the intended duration oftreatment. Thus, in the case of onychomycosis, the dosing regimen willgenerally be tailored so that tissue levels of the administeredantifungal agent correlate to the minimal inhibitory concentration (MIC)for the suspected infecting agent (obtained by in vitro testing). Forexample, the MIC concentrations listed in Table 1 may be used indeveloping the dosing regimen (Karaca et al. Diagnostic Microbiology andInfectious Disease 48: 259-264 (2004), herein incorporated by referencein its entirety).

TABLE 1 Exemplary In Vitro MIC Concentrations for Select Fungal SpeciesMIC Ranges Anti-Fungal Agent Fungal Species (mcg/ml) FluconazoleTrichophyton rubrum <0.06->32   Trichophyton mentagrophytes 16-32Trichophyton tonsurans 0.25-8   Trichophyton verrucosum 16 KetoconazoleTrichophyton rubrum <0.008->4    Trichophyton mentagrophytes 0.008-4   Trichophyton tonsurans 0.016-0.125 Trichophyton verrucosum 4Itraconazole Trichophyton rubrum <0.001-1    Trichophyton mentagrophytes0.008-0.06  Trichophyton tonsurans ≦0.001-0.5    Trichophyton verrucosum1 Sulconazole Trichophyton rubrum <0.008-4    Trichophytonmentagrophytes 0.016-0.125 Trichophyton tonsurans ≦0.008-0.03 Trichophyton verrucosum 4 Oxiconazole Trichophyton rubrum <0.0008-2    Trichophyton mentagrophytes 0.06-0.5  Trichophyton tonsurans≦0.0008-2     Trichophyton verrucosum 4 Bifonazole Trichophyton rubrum<0.016-1    Trichophyton mentagrophytes 0.125-0.25  Trichophytontonsurans ≦0.016-0.5    Trichophyton verrucosum 8 MiconazoleTrichophyton rubrum 0.008-4    Trichophyton mentagrophytes 1Trichophyton tonsurans 0.016-0.25  Trichophyton verrucosum 4 TerbinafineTrichophyton rubrum ≦0.0001-1     Trichophyton mentagrophytes ≦0.001Trichophyton tonsurans ≦0.001-0.008  Trichophyton verrucosum 1Griseofulvin Trichophyton rubrum 0.016-8    Trichophyton mentagrophytes0.016-0.125 Trichophyton tonsurans 0.5-1   Trichophyton verrucosum 1Ciclopiroxolamine Trichophyton rubrum <0.03-8    Trichophytonmentagrophytes 0.5-1   Trichophyton tonsurans 0.125-1    Trichophytonverrucosum 4

Other substances may be included in the compositions for a variety ofpurposes. For example, buffering agents and preservatives may beemployed. Preservatives which may be used include, but are not limitedto, sodium bisulfite, sodium bisulfate, sodium thiosulfate, benzalkoniumchloride, chlorobutanol, thimerosal, phenylmercuric acetate,phenylmercuric nitrate, methylparaben, polyvinyl alcohol and phenylethylalcohol. Examples of buffering agents that may be employed include, butare not limited to, sodium carbonate, sodium borate, sodium phosphate,sodium acetate, sodium bicarbonate, and the like, as approved by the FDAfor the desired route of administration. Electrolytes such as sodiumchloride and potassium chloride may also be included in thecompositions.

Administration. One or more drug delivery systems may be inserted intothe distal portion of a digit or into any portion of the nail unit by avariety of methods, including placement using forceps, conduits such astrocars and needles, and applicators configured to drive the systemdirectly into the skin. The conduit may be configured to be malleable.If desired, the conduit, e.g., a needle, may also be adapted so that aportion of it can remain at the target site after injection. Forexample, the distal end of the needle may be configured such that it canseparate from the rest of the needle.

The conduit or applicator may be preloaded with one or more drugdelivery systems. In one variation, the drug delivery system(s) mayreside within a conduit lumen. In another variation, the drug deliverysystem(s) may be incorporated on the tip of a sharp-tipped applicator orprovided in a cartridge to be used with an applicator, e.g., a springpowered applicator.

In one variation, the method of implantation generally first involvesaccessing the target area within the distal portion of the digit withthe conduit. Once within the target area, e.g., the germinal matrix, apush rod, pressurized gas, or jet injection may be used to push the drugdelivery system out of the conduit into the target area. In general, thedrug delivery system is placed in or in close proximity to the areaaffected by the nail condition. Thus, if onychomycosis is the nailcondition being treated, the drug delivery system is usually placed ator in close proximity to the germinal matrix to allow uptake of theactive agent into the growing nail. Similarly, if paronychia is the nailcondition being treated, the drug delivery system is usually placed ator in close proximity to the proximal nail fold. After delivery to thetarget area, the drug delivery systems do not undergo a phase change dueto changes in temperature, e.g., upon reaching body temperature.

Although the drug delivery systems have been described as being placedwithin the nail unit or within the distal portion of a digit, the methodof administration is not so limited. If desired, the drug deliverysystems may be placed within the tissue of any part of a digit to treatconditions affecting those parts. For example, they may be placed withina middle portion of a digit and/or a proximal portion of a digit. Themiddle portion of a digit generally refers to those tissues orstructures surrounding the middle phalanx (second phalanx). The proximalportion of a digit generally refers to those tissues or structuressurrounding the proximal phalanx (first phalanx) and/or a metacarpalbone.

Applications. Examples of nail unit conditions that may be treated withthe described drug delivery systems include, but are not limited to,medical conditions such as infections, inflammation, and tumors.Examples of nail infections include, but are not limited to, distal andlateral subungual onychomycosis, endonyx onychomycosis, whitesuperficial onychomycosis, proximal subungual onychomycosis, totaldystrophic onychomycosis, Candida onychomycosis, and paronychia.Examples of nail inflammation include, but are not limited to thoseconditions associated with inflammatory diseases such as psoriasis andlichen planus. Examples of nail tumors include, but are not limited to,glomus tumor, digital myxoid (mucus) cyst, subungual exostosis, andperiungual angiofibromas. The drug delivery systems may also be used totreat cosmetic nail unit conditions such as pitting, brittleness, ordiscoloration.

EXAMPLES

The following examples serve to more fully describe the manner of makingand using the above-described compositions. It is understood that theseexamples in no way serve to limit the scope of this invention, butrather are presented for illustrative purposes.

Unless otherwise indicated, the substances used in the examples wereobtained from the sources listed below:

Aldrich Chemicals, Milwaukee, Wis.

Vancomycin

Dow Chemical, Midland, Mich.

HPMC

PEG 3350

Eastman Chemicals, Llangefni, Anglesey, UK

Vitamin E TPGS

EMD Chemicals, Darmstadt, Germany

EDTA

Fluka, Allentown, Pa.

Ciprofloxacin

JT Baker, Phillpsburg, N.J.

Carbamide

Lakeshore Biomaterials, Birmingham, Ala.

PLGA

Norland High Molecular Weight Fish Gelatin, Cranbury, N.J.

Gelatin

Recordati Espana S. LI, Beniel (Murcia)

Fluconazole

Itraconazole

Recordati S.p.A., Milano, Italy

Terbinafine

Sigma-Aldrich, Saint Louis, Mo.

Dexamethasone

Ketorolac

Lidocaine

Poly(vinyl alcohol)

Spectrum Chemical Mfr., Gardena, Calif.

Vitamin E succinate

Furthermore, the following examples will employ, unless otherwiseindicated, conventional techniques of pharmaceutical formulation,medicinal chemistry, and the like, which are within the skill of theart. Such techniques are explained fully in the literature. Efforts havebeen made to ensure accuracy with respect to numbers (e.g., amounts,temperature, etc.), but some experimental error and deviation should beaccounted for. Unless indicated otherwise, parts are parts by weight,temperature is in degrees Celsius (° C.) and pressure is at or nearatmospheric pressure at sea level. All components are obtainablecommercially unless otherwise indicated.

Example 1 Preparation of Terbinafine Microparticles and In Vitro Releaseof Terbinafine

A predetermined amount of the drug terbinafine HCl (3.3 g) is added tothe oil phase (polymer in solvent 5.0 g/7.0 g). The polymer is 50/50polylactic acid/glycolic acid with a molecular weight of about 40,000g/mol, and the solvent is methylene chloride. The aqueous phase (23.5 g)contains the emulsifier polyvinyl alcohol (2.5 g) to adjust viscosity.Approximately three drops of octanol is added to the aqueous phase toprevent or minimize foaming. Furthermore, to prevent drug loss into theaqueous phase, the aqueous phase is saturated with the drug.

Next, a one inch impeller mixer is used to agitate the continuous phaseat about 600 rpm. The oil phase is then slowly added to the aqueousphase. This mixture is stirred for about an hour, and air passed over itto remove the evaporating solvent. After ten minutes, the stirrer speedis reduced to 400 rpm. At about 30 minutes, most of the methylenechloride will have evaporated and the emulsion droplets solidified.Agitation is continued at about 60 rpm for another 45 minutes to preventagglomeration. The solidified microparticles are then separated from theaqueous solution using a vacuum funnel and filter paper. After continuedwashing to remove any emulsifier, the microparticles are dried andsieved. Only particles smaller than 400 microns are kept. By adjustingthe continuous phase stirring speed, the yield in different particlesize classes can be adjusted.

Terbinafine release from the microparticles can then be measured asfollows. Large terbinafine microparticles of about 330 micron radiusmade according to the method described above are placed into screw capglass vials filled with 10 ml of phosphate buffered saline (PBS) andplaced into a shaking water bath kept at a temperature of 35° C. Aftercentrifuging, samples of 1.0 ml are removed at designated time pointsand replaced with the same amount of fresh PBS. The samples are thenanalyzed for drug concentration by techniques known in the art, such asspectroscopy, HPLC, mass spectroscopy, and the like. Thesemicroparticles are expected to have a drug release profile as shown inthe following table:

Time Day 2 Day 14 Day 30 Day 60 % release 10-15 30-35 70-75 90-95

The microparticles generally provide high initial drug release (burstrelease). This is desirable, for example, to load up the tissue quicklyand prevent shedding of conidia in the early days of injection.Subsequent drug release would be fashioned to be at a lower rate, butwould be sufficient to maintain the appropriate minimum inhibitoryconcentration (MIC) and/or minimal fungicidal concentration (MFC) of theantifungal agent.

Example 2 Itraconazole Microparticles and In Vitro Release ofItraconazole

Microparticles including itraconazole are prepared according to themethod described in Example 1 at a size of about 400 microns. In vitrodrug release is measured in the same manner as Example 1. Thesemicroparticles are expected to have a drug release profile as shown inthe following table:

Time Day 2 Day 14 Day 30 Day 45 % release 20-25 60-65 80-85 95-100

Example 3 Ciprofloxacin Microparticles and In Vitro Release ofCiprofloxacin

Microparticles are prepared as described in Example 1, except thatciprofloxacin is added instead of terbinafine. The size of themicroparticles should be about 250 microns. These microparticles areexpected to have a drug release profile as shown in the following table:

Time Day 1 Day 2 Day 14 Day 30 % release 20-25 30-35 70-75 90-95

These microparticles provide a high initial burst of active agent, whichwould, in the clinical environment, generate locally high anti-infectiveconcentration levels. This is desirable, for example, after surgery, toprevent microorganisms that may be introduced during the surgicalprocedure from replicating and causing an infection of the wound area.Subsequent drug release would be lower, but sufficient to generate an invivo maintenance level that can prevent the microbial re-colonization ofthe surgical area. At day 7, it is believed that the cumulative drugrelease will equal the theoretical drug-loading amount.

Example 4 Terbinafine Solid Drug Delivery Systems

Preparation of a Terbinafine Drug Delivery System May be Accomplished bywetting 2.0 g of Metolose SR (90SH, 100000SR, methylcellulose, Shin-EtsuChemical Co., Ltd., Tokyo) with 2.0 g of water. To that paste is added4.5 g of terbinafine. After thorough mixing, the resulting paste is thenmolded into a flat film of about 0.4 mm thickness using a carver press.The pressed film is then cut into about 1.0 mm², about 2.0 mm², or about5.0 mm² discs using thin walled Teflon straws. Square-based columns canalso be cut from the film of desired length and width by first trimmingthe pressed film and then cutting it to the desired width. The discs orsquare-based rod like systems are then dried overnight in a vacuum oven.

In another variation, the terbinafine drug delivery system may be formedas a strip. A saturated solution of gelatin in water is prepared.Micronized terbinafine is added to achieve a mixture having a polymer todrug ratio of 30:70. The resulting mixture is poured onto a glass platecovered with a standard silicone coated polyester release liner. Agardener knife is used to create about a 300 mm thick film. The glassplate with the resulting film is placed into a vacuum oven and driedovernight at 80° C. The resulting film is then cut into strips ofdesired length and width.

Example 5 Vancomycin Solid Drug Delivery Systems

Vancomycin drug delivery systems may be made by wetting 2.0 g ofMetolose SR with 2.0 grams of water. To that paste is added 3.6 g ofvancomycin. After thorough mixing, the resulting paste is then moldedinto a flat film of about 1.0 mm thickness using a carver press. Thepressed film is then cut into about 1.0 mm², about 2.0 mm², or about 5.0mm² discs using thin walled Teflon straws. Square-based columns can alsobe cut from the film of desired length and width by first trimming thepressed film and then cutting it to the desired width. The discs orsquare-based rod like systems are then dried overnight in a vacuum oven.

In another variation, the vancomycin drug delivery systems are made bywetting 2.0 g of L-HPC (LH-20, low-substituted hydroxypropylcellulose)(Shin-Etsu Chemical Co., Ltd., Tokyo, Japan) with 2.0 g of water. Tothat paste is added 3.6 g of vancomycin. After thorough mixing, theresulting paste is then molded into a flat film of about 1.0 mmthickness using a carver press. The pressed film is then cut into about1.0 mm², about 2.0 mm², or about 5.0 mm² discs using thin walled Teflonstraws. Square-based columns can also be cut from the film of desiredlength and width by first trimming the pressed film and then cutting itto the desired width. The discs or square-based rod like systems arethen dried overnight in a vacuum oven.

Example 6 Itraconazole Solid Drug Delivery System

Itraconazole drug delivery systems may be made by wetting 2.0 g ofMetolose SR with 2.0 g of water. To that paste is added 4.0 g ofitraconazole. After thorough mixing, the resulting paste is then moldedinto a flat film of about 1.0 mm thickness using a carver press. Thepressed film is then cut into about 1.0 mm², about 2.0 mm², or about 5.0mm² discs using thin walled Teflon straws. Square-based columns can alsobe cut from the film of desired length and width by first trimming thepressed film and then cutting it to the desired width. The discs orsquare-based rod like systems are then dried overnight in a vacuum oven.

Example 7 Dexamethasone Solid Drug Delivery System

Dexamethasone drug delivery systems may be formed by wetting 2.0 g ofL-HPC 2.0 g of water. To that paste is added 4.0 g of dexamethasone.After thorough mixing, the resulting paste is then molded into a flatfilm of about 1.0 mm thickness using a carver press. The pressed film isthen cut into about 1.0 mm², about 2.0 mm², or about 5.0 mm² discs usingthin walled Teflon straws. Square-based columns can also be cut from thefilm of desired length and width by first trimming the pressed film andthen cutting it to the desired width. The discs or square-based rod likesystems are then dried overnight in a vacuum oven.

Example 8 Lidocaine Solid Drug Delivery System

Lidocaine drug delivery systems may be made by wetting 2.0 g of MetoloseSR with 2.0 g of water. To that paste is added 2.0 g of lidocaine. Afterthorough mixing, the resulting paste is then molded into a flat film ofabout 1.0 mm thickness using a carver press. The pressed film is thensprayed on one side with a solution of 0.5 wt % CA-398-10NF solution inacetone. Strips of about 3.0 mm by about 5.0 mm are then cut and driedovernight in a vacuum oven.

Example 9 Ketorolac Solid Drug Delivery System

Ketorolac drug delivery systems may be formed by first preparing asaturated solution of hyaluronic acid in water. Micronized S(−)ketorolacis then added to the solution to achieve a mixture having a polymer todrug ratio of 40:60. The resulting mixture is poured onto a glass platecovered with a standard silicone coated polyester release liner. Agardener knife is used to spread the mixture and create about a 300 mmthick film. The glass plate with the resulting film is placed into avacuum oven and dried overnight at 80° C. The resulting film is then cutinto strips of desired length and width.

Example 10 Methadone Solid Drug Delivery System

Methadone drug delivery systems may be formed by first preparing asaturated solution of hyaluronic acid in water. Micronized R(−)methadoneis then added to the solution to achieve a mixture having a polymer todrug ratio of 40:60. The resulting mixture is poured onto a glass platecovered with a standard silicone coated polyester release liner. Agardener knife is used to spread and create about a 300 mm thick film.The glass plate with the resulting film is placed into a vacuum oven anddried overnight at 80° C. The resulting film is then cut into strips ofdesired length and width.

Example 11 Combination Dexamethasone and Itraconazole Drug DeliverySystems

Combination dexamethasone and itraconazole drug delivery systems may bemade by wetting 2.0 g of AQOAT Enteric Coating Agent (AS/HF,hydroxypropylmethyl cellulose acetate succinate) (Shin-Etsu ChemicalCo., Ltd., Tokyo, Japan) with 2 g of water. To that paste is added 1.5 gof dexamethasone and 3.5 g of itraconazole. After thorough mixing, theresulting paste is then molded into a flat film of about 1.0 mmthickness using a carver press. The pressed film is then cut into about1.0 mm², about 2.0 mm², or about 5.0 mm² discs using thin walled Teflonstraws. Square-based columns can also be cut from the film of desiredlength and width by first trimming the pressed film and then cutting itto the desired width. The discs or square-based rod like systems arethen dried overnight in a vacuum oven.

In another variation, the combination dexamethasone and itraconazoledrug delivery systems may be made by wetting 2.0 g of gelatin with 2.0 gof water. To that paste is added 1.5 g of dexamethasone and 3.0 g ofitraconazole. After thorough mixing, the resulting paste is then moldedinto a flat film of about 1.0 mm thickness using a carver press. Thepressed film is then cut into about 1.0 mm², about 2.0 mm², or about 5.0mm² discs using thin walled Teflon straws. Square-based columns can alsobe cut from the film of desired length and width by first trimming thepressed film and then cutting to the desired width. The discs orsquare-based rod like systems are then dried overnight in a vacuum oven.

Example 12 Combination Dexamethasone and Ciprofloxacin Drug DeliverySystem

Combination dexamethasone and ciprofloxacin drug delivery systems may beformed by wetting 2.0 g of gelatin with 2.0 g of water. To that paste isadded 1.5 grams dexamethasone and 1.5 g of ciprofloxacin. After thoroughmixing, the resulting paste is then molded into a flat film of about 1.0mm thickness using a carver press. The pressed film is then cut intoabout 1.0 mm², about 2.0 mm², or about 5.0 mm² discs using thin walledTeflon straws. Square-based columns can also be cut from the film ofdesired length and width by first trimming the pressed film and thencutting to the desired width. The discs or square-based rod like systemsare then dried overnight in a vacuum oven.

Example 13 Dexamethasone Extruded Drug Delivery System

One gram of a well-mixed powder of dexamethasone and 50/50 polylacticacid/polyglycolic acid copolymer with an inherent viscosity of 0.24 wasmeasured and filled into a batch extruder and heated for one hour at 95°C. The melt was then extruded through a circular orifice to create afilament having a diameter of about 0.4 mm. From the filament, variouslength subunits were cut and tested for in vitro drug release using theUSP Paddle apparatus, in PBS, pH 7.4. Dexamethasone release from a 2.2mm long filament extruded through a 400 um circular orifice is shown inthe following table:

Time Day 1 Day 2 Day 14 Day 30 % release 19 30 69 89

Example 14 Terbinafine Extruded Drug Delivery Systems—70% TerbinafineLoading

PEG Matrix. The terbinafine extruded delivery system was made by firstmixing terbinafine HCl and PEG at a ratio of 70:30 respectively (totalweight of the mixture was 0.5 g). The mixture was filled into a batchextruder and heated for one hour at 115° C. The melt was then extrudedthrough a circular orifice to create a filament having a diameter ofabout 0.4 mm. From the filament, various length subunits were cut andtested for in vitro drug release, as described in Example 1, except thatinstead of removing 1.0 ml per sample, 8.0 ml was removed per sample.Sample pH measured 7.4. Terbinafine release from a 3.0 mm long filamentis shown in the following table:

Time Day 1 Day 2 Day 14 Day 30 % release 4 91 100 100

PEG/Vitamin E TPGS Matrix. The terbinafine extruded delivery system wasmade by first preparing a well-mixed powder containing terbinafine HCl,PEG 3350, and D-α-tocopheryl polyethylene glycol 1000 succinate (vitaminE TPGS) at a ratio of 70:15:15, respectively (total weight of themixture was 0.25 g). The well-mixed powder was filled into a batchextruder and heated for 1 hour at 115° C. The melt was then extrudedthrough a circular orifice to create a filament having a diameter ofabout 330 um. From the filament, various length subunits were cut andtested for in vitro drug release, as described in Example 1. As above,the receptor medium was PBS and the volume removed per sample was 8 ml.The pH of the samples was 7.4. Terbinafine release from a 3.0 mm longfilament is shown in the following table.

Time Day 1 Day 2 Day 14 Day 30 % release 18 22 37 50

PEG/PLGA Matrix. The terbinafine extruded delivery system was made byfirst preparing a mixture of terbinafine HCl, PEG, and PLGA at a ratioof 70:15:15, respectively (total weight of the mixture was 0.25 g). Thewell-mixed powder was filled into a batch extruder and heated for 1 hourat 115° C. The melt was then extruded through a circular orifice tocreate a filament having a diameter of about 330 um. From the filament,various length subunits were cut and tested for in vitro drug release,as described in Example 1. As above, the receptor medium was PBS and thevolume removed per sample was 8 ml. The pH of the samples was 7.4.Terbinafine release from a 3.0 mm long filament is shown in thefollowing table:

Time Day 1 Day 2 Day 14 Day 30 % release 4 7 32 52

In yet another variation, the terbinafine extruded delivery system wasmade by first preparing a mixture of terbinafine HCl, PLGA, and PEG at aratio of 70:20:10 (total weight of the mixture was 0.25 g). Thewell-mixed powder was filled into a batch extruder and heated for 1 hourat 115° C. The melt was then extruded through a circular orifice tocreate a filament having a diameter of about 415 um. From the filament,various length subunits were cut and tested for in vitro drug release,as described in Example 1. As above, the receptor medium was PBS and thevolume removed per sample was 8 ml. The pH of the samples was 7.4.Terbinafine release from a 3.0 mm long filament is shown in thefollowing table:

Time Day 1 Day 2 Day 14 Day 30 % release 1 3 11 22

PLGA/Vitamin E Succinate Matrix. The terbinafine extruded deliverysystem was made by first preparing a mixture of terbinafine HCl, PLGA,and vitamin E succinate at a ratio of 70:27.5:2.5, respectively (totalweight of the mixture was 0.25 g). The well-mixed powder was filled intoa batch extruder and heated for 1 hour at 115° C. The melt was thenextruded through a circular orifice to create a filament having adiameter of about 415 um. From the filament, various length subunitswere cut and tested for in vitro drug release, as described inExample 1. As above, the receptor medium was PBS and the volume removedper sample was 8 ml. The pH of the samples was 7.4. Terbinafine releasefrom a 3.0 mm long filament is shown in the following table:

Time Day 1 Day 2 Day 14 Day 30 % release 1 3 5 15

Vitamin E Succinate/PEG 3350 Matrix. The terbinafine extruded deliverysystem was made by first preparing a mixture of terbinafine HCl, vitaminE succinate, and PEG 3350 at a ratio of 70:15:15, respectively (totalweight of the mixture was 0.25 g). The well-mixed powder was filled intoa batch extruder and heated for 1 hour at 115° C. The melt was thenextruded through a circular orifice to create a filament having adiameter of about 415 um. From the filament, various length subunitswere cut and tested for in vitro drug release, as described inExample 1. As above, the receptor medium was PBS and the volume removedper sample was 8 ml. The pH of the samples was 7.4. Terbinafine releasefrom a 3.0 mm long filament is shown in the following table:

Time Day 1 Day 2 Day 14 Day 30 % release 16 22 100 100

PLGA/Dimethyl Sulfone Matrix. The terbinafine extruded delivery systemwas made by first preparing a mixture of terbinafine HCl, PLGA, anddimethyl sulfone at a ratio of 70:25:5, respectively (total weight ofthe mixture was 0.25 g). The well-mixed powder was filled into a batchextruder and heated for 1 hour at 115° C. The melt was then extrudedthrough a circular orifice to create a filament having a diameter ofabout 415 um. From the filament, various length subunits were cut andtested for in vitro drug release, as described in Example 1. As above,the receptor medium was PBS and the volume removed per sample was 8 ml.The pH of the samples was 7.4. Terbinafine release from a 3.0 mm longfilament is shown in the following table:

Time Day 1 Day 2 Day 14 Day 30 % release 1 2 8 15

Carbamide Matrix. The terbinafine extruded delivery system was made byfirst preparing a mixture of terbinafine HCl and carbamide at a ratio of70:30, respectively (total weight of the mixture was 0.25 g). Thewell-mixed powder was filled into a batch extruder and heated for 1 hourat 115° C. The melt was then extruded through a circular orifice tocreate a filament having a diameter of about 415 um. From the filament,various length subunits were cut and tested for in vitro drug release,as described in Example 1. As above, the receptor medium was PBS and thevolume removed per sample was 8 ml. The pH of the samples was 7.4.Terbinafine release from a 3.0 mm long filament is shown in thefollowing table:

Time Day 1 Day 2 Day 14 Day 30 % release 1 2 11 19

Example 15 Terbinafine Extruded Drug Delivery System—80% TerbinafineLoading

The terbinafine extruded delivery system was made by first mixingterbinafine HCl and PEG as the matrix-forming material at a ratio of80:20 respectively (total weight of the mixture is 0.5 g). The mixturewas filled into a batch extruder and heated for one hour at 115° C. Themelt was then extruded through a circular orifice to create a filamenthaving a diameter of about 0.4 mm. From the filament, various lengthsubunits were cut and tested for in vitro drug release, as described inExample 1, except that instead of removing 1.0 ml per sample, 8.0 ml wasremoved per sample. Sample pH measured 7.4. Terbinafine release from a3.0 mm long filament is shown in the following table:

Time Day 1 Day 2 Day 14 Day 30 % release 38 100 100 100

Example 16 Fluconazole Extruded Drug Delivery Systems—80% FluconazoleLoading

The fluconazole extruded delivery system was made by first mixingfluconazole and PEG as the matrix-forming material at a ratio of 80:20respectively (total weight of the mixture is 0.5 g). The mixture wasfilled into a batch extruder and heated for one hour at 115° C. The meltwas then extruded through a circular orifice to create a filament havinga diameter of about 0.4 mm. From the filament, various length subunitswere cut and tested for in vitro drug release, as described in Example1, except that instead of removing 1.0 ml per sample, 8.0 ml was removedper sample. Sample pH measured 7.4. Terbinafine release from a 3.0 mmlong filament is shown in the following table:

Time Day 1 Day 2 Day 14 Day 30 % release 60 100 100 100

Example 17 Itraconazole Extruded Drug Delivery System

The itraconazole extruded delivery system was made by first mixingitraconazole and PEG as the matrix-forming material at a ratio of 80:20respectively (total weight of the mixture is 0.5 g). The mixture wasfilled into a batch extruder and heated for one hour at 115° C. The meltwas then extruded through a circular orifice to create a filament havinga diameter of about 0.4 mm. From the filament, various length subunitswere cut and tested for in vitro drug release, as described in Example1, except that instead of removing 1.0 ml per sample, 8.0 ml was removedper sample. Sample pH measured 7.4. Terbinafine release from a 3.0 mmlong filament is shown in the following table:

Time Day 1 Day 2 Day 14 Day 30 % release 30 100 100 100

Example 18 Ketorolac Extruded Drug Delivery System

One gram of well-mixed powder containing the active agent S(−)ketorolacand 50/50 polylactic acid/polyglycolic acid copolymer with an averagemolecular weight of 20,000 g/mol at a ratio of 50:50 is first prepared.The well-mixed powder is then filled into a batch extruder and heatedfor 1 hour at 115° C. The melt is extruded through a circular orifice tocreate a filament having a diameter of about 0.33 mm. Subunits ofvarious lengths may then be cut from the filament.

Example 19 Methadone Extruded Drug Delivery System

Methadone extruded drug delivery systems may be made by first mixingR(−) methadone with a 50/50 polylactic acid/polyglycolic acid copolymerwith an average molecular weight of 45,000 g/mol at a ratio of 60:40,respectively (total weight of the mixture is 0.5 g). The well-mixedpowder is filled into a batch extruder and heated for 1 hour at 115° C.The melt is then extruded through a circular orifice to create afilament having a diameter of about 0.9 mm. Subunits of various lengthsmay then be cut from the filament.

Example 20 Clindamycin Extruded Drug Delivery System

Clindamycin extruded drug delivery systems may be made by mixingclindamycin and a 50/50 polylactic acid/polyglycolic acid copolymer withan average molecular weight of 20,000 g/mol at a ratio of 50:50 (totalweight of the mixture is 0.5 g). The well-mixed powder is filled into abatch extruder and heated for 1 hour at 115° C. The melt is thenextruded through a circular orifice to create a filament having adiameter of about 0.5 mm diameter. Subunits of various lengths may thenbe cut from the filament.

Example 21 Gancyclovir Extruded Drug Delivery System

One gram of well-mixed powder of ganciclovir and a 50/50 polylacticacid/polyglycolic acid copolymer with an average molecular weight of50,000 g/mol at a ratio of 80:20, respectively, is prepared. Thewell-mixed powder is filled into a batch extruder and heated for 1 hourat 110° C. The melt is then extruded through a circular orifice tocreate a filament having a diameter of about 1.1 mm. The extrudedfilament sections are dipped into a 3-wt % aqueous solution ofPharmacoat 615. The coated filament sections are then dried overnight ina vacuum oven at room temperature. Subunits of various lengths may thenbe cut from the overcoated filament.

Example 22 Combination Dexamethasone and Vitamin E Extruded DrugDelivery Systems

Combination dexamethasone and vitamin E extruded drug delivery systemsmay be made by mixing the vitamin E ester d-α-tocopheryl acetate withdexamethasone powder in a ratio of 50:50 and then extruding the mixturethrough a round orifice having a diameter of about 0.5 mm at atemperature of 50° C. The melt is then sub-divided into dosage units ofvarious lengths and cooled overnight.

In another variation, the vitamin E ester d-α-tocopheryl succinate ismixed with dexamethasone powder in a ratio of 50:50 and then extrudedthrough a round orifice having a diameter of about 0.5 mm at atemperature of 90° C. The melt is then sub-divided into dosage units ofvarious lengths and cooled overnight.

Example 23 Terbinafine Liquid Drug Delivery System

Carbamide and Terbinafine were mixed at ratios of 70:30, 60:40, 50:50,40:60, and 30:70, respectively, and then heated in small HPLC glassvials up to 170° C. The resulting liquid was tested for injectionfeasibility. Tests were conducted to explore the physical properties ofthe solution as a function of temperature.

Example 24 Free-Base Terbinafine

An aqueous solution of terbinafine HCl may be reacted with sodiumhydroxide at a pH of 7.5 to 13.0 to form the freebase (base) form of thedrug. The free base form is to form an oily solution that can bedelivered to the site in this form. A mixture of the free base and thesalt may also be employed.

Example 25 Terbinafine Microparticles—Less Than 30% Terbinafine Loadingand In Vitro Release of Terbinafine

Microparticles including terbinafine are prepared according to themethod described in Example 1. In order to decrease the size of theaverage microparticle to about 50-100 um, the stirrer speed may beadjusted to a higher rpm, for example, 1250-1500 rpm. These smallersized microparticles are expected to have a better penetration profileif the method of administration involves pushing the microparticles intoand/or through the skin, e.g., by using a push rod, pressurized gas, jetinjection, and the like. Additionally, to increase the duration of drugrelease, a polymer of higher molecular weight, for example, 75,000g/mol, may be used. To further control drug release the load in themicroparticle may be dropped by using a smaller drug to polymer ratio(e.g., 1.5 g drug/5 g polymer). In vitro drug release may then bemeasured in the same manner as Example 1. These microparticles areexpected to have a drug release profile as shown in the following table:

Time Day 2 Day 21 Day 45 Day 70 % release 20-25 50-55 80-85 95-100

All publications, patents, and patent applications cited herein arehereby incorporated by reference in their entirety for all purposes tothe same extent as if each individual publication, patent, or patentapplication were specifically and individually indicated to be soincorporated by reference. Although the foregoing compositions andmethods have been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to those of ordinary skill in the art in light of thisdescription that certain changes and modifications may be made theretowithout departing from the spirit and scope of the appended claims.

1-76. (canceled)
 77. A local sustained release drug delivery implant fortreating a fungal infection of a nail, comprising a single bioerodiblepolymer and an antifungal agent, and wherein the implant is a solid,having a volume from between greater than 0 mm³ to about 20 mm³, and issized and shaped for implantation into a tissue of the distal phalanx,and is configured to release the active agent over a period of at leasttwo weeks, and does not undergo a phase change with a change intemperature.
 78. The drug delivery implant of claim 77 wherein thefungal infection is onychomycosis.
 79. The drug delivery implant ofclaim 77 wherein the non-temperature phase change composition comprisesthe active agent in crystalline form.
 80. The drug delivery implant ofclaim 77 further comprising an additional active agent, wherein theadditional active agent is selected from the group consisting ofanalgesics, anesthetics, anti-infective agents, anti-inflammatoryagents, chemotherapeutic agents, nucleic acids, peptides, proteins, andcombinations thereof.
 81. The drug delivery implant of claim 80 whereinthe additional active agent comprises an anti-infective agent.
 82. Thedrug delivery implant of claim 81 wherein the anti-infective agent isselected from the group consisting of antibacterial agents, antifungalagents, antiviral agents, antiseptics, and combinations thereof.
 83. Thedrug delivery implant of claim 77 wherein the antifungal agent isselected from the group consisting of amorolfine, ciclopirox,flucytosine, griseofulvin, haloprogrin, potassium iodide sodiumpyrithione, undecylenic acid, imidazole derivatives, triazolederivatives, allylamines, polyene antifungal antibiotics, antifungalorganic acids, and combinations thereof.
 84. The drug delivery system ofclaim 83 wherein the imidazole derivative is selected from the groupconsisting of bifonazole, butoconazole, clotrimazole, econazole,ketoconazole, miconazole, oxiconazole, sulconazole, and combinationsthereof.
 85. The drug delivery system of claim 83 wherein the triazolederivative is selected from the group consisting of itraconazole,fluconazole, terconazole, and combinations thereof.
 86. The drugdelivery implant of claim 83 wherein the allylamine comprisesterbinafine.
 87. The drug delivery implant of claim 77 comprising lessthan 30% active agent by weight.
 88. The drug delivery implant of claim77 wherein the implant is sized and shaped for injection into the tissueof the distal phalanx.
 89. The drug delivery implant of claim 77 whereinrelease of the antifungal agent is over a period of at least four weeks.90. The drug delivery implant of claim 77 wherein release of theantifungal agent is over a period of at least eight weeks.
 91. The drugdelivery implant of claim 77 wherein release of the antifungal agent isover a period of at least twelve weeks.
 92. The drug delivery implant ofclaim 77 wherein the implant is formed as a particle, sheet, disc,filament, or rod.
 93. A method for treating a nail unit conditioncomprising administering within a digit a non-temperature dependentphase change composition having a therapeutically effective amount of anactive agent for sustained release.
 94. The method of claim 93 whereinthe nail unit condition is a onychomycosis.
 95. The method of claim 93wherein the digit is a finger or a toe.
 96. The method of claim 93wherein the active agent is selected from the group consisting ofanalgesics, anesthetics, anti-infective agents, anti-inflammatoryagents, chemotherapeutic agents, nucleic acids, peptides, proteins, andcombinations thereof.